Isosorbide dinitrate-containing patches are commonly known, and it is indicated, for example, in Japanese Unexamined Patent Publication No. 57-116011, etc., that pressure-sensitive adhesives such as silicone-based, rubber-based or acrylic-based adhesives are preferable as pressure-sensitive adhesives used in these patches. In addition, at the 5th meeting of the Japan Pharmacology Association (Sep. 26-28, 1989), Oguche, et al. reported that with respect to patches containing isosorbide dinitrate, they compared acrylic-based, silicone-based and rubber-based adhesives with each other and found the percutaneous absorption of these three are roughly equal.
The above-mentioned Japanese Unexamined Patent Publication No. 57-116011 was later published after examination (Japanese Examined Patent Publication No. 4-74329) with an amendment stating that acrylic-based pressure-sensitive adhesives are particularly preferable among various types of pressure-sensitive adhesives.
Namely, in conventional isosorbide dinitrate-containing patches, with respect to the relationship between the percutaneous absorption of isosorbide dinitrate and the pressure-sensitive adhesive, it was considered that acrylic-based adhesives are preferable, or that the above-mentioned acrylic-based adhesives and rubber-based adhesives are equally preferable.
One of the shortcomings of patches is the occurrence of rashes on the skin, and various proposals have been made as methods to suppress it. One method involves reducing the size of the preparation so that the portion of the skin where the rash occurs will be smaller. However, it is necessary to increase the amount of percutaneous absorption per unit area in order to accomplish this. Although various types of absorption promoters were proposed for adding to a patch (an adhesive layer) in order to increase the amount of percutaneous absorption, due in part to the fact that absorption promoters generally have a low molecular weight, they often demonstrate skin irritation. In addition, there are also problems including a decrease in the adhesive strength of the resultant adhesive composition when large amounts of absorption promoters are added. Thus, a patch that suppresses the occurrence of skin rash while also offering excellent percutaneous absorption and adhesive strength has not been successfully provided yet.
For example, for the purpose of providing an isosorbide dinitrate-containing patch good in balance between adhesivity and skin irritation, a patch prepared by adding isopropyl myristate in a large amount as a plasticizing component to an acrylic-based adhesive has been proposed (Japanese Unexamined Patent Publication No. 3-223212). However, since an acrylic-based adhesive is not sufficiently good in compatibility with isosorbide dinitrate, isosorbide dinitrate as crystals in an adhesive layer when the concentration of isosorbide dinitrate is higher than about 10-15% by weight. Even in the case of such a high content of isosorbide dinitrate, therefore it is considered that the promotion effect in percutaneous absorption is little, and the main effect is only the extension of releasing time.
In order to increase absorbability, it is desirable to use an adhesive composition capable of dissolving isosorbide dinitrate in high concentration, and it has been discovered that polyvinyl acetate-based adhesives are preferable as such adhesive composition (Japanese Unexamined Patent Publication No. 6-329539, Japanese Unexamined Patent Publication No. 6-345640 and International Publication No. WO95-22970).
Such polyvinyl acetate-based adhesives have demonstrated superior promotion effect on percutaneous absorption to conventional pressure-sensitive adhesives. However, when an isosorbide dinitrate-containing patch is compared with a glycerol nitrate-containing patch, in which both the active ingredients are typical percutaneous coronary vasodilators, a minimum-sized isosorbide dinitrate-containing patch on market is 30 cm.sup.2 while a minimum-sized glycerol nitrate-containing patch on market is 20 cm.sup.2. Namely, for increasing the percutaneous absorption of isosorbide dinitrate from an isosorbide dinitrate-containing patch in such a degree that the compliance of a patient is improved, further improvement in percutaneous absorption is required. This improvement enables the downsizing of patches so that skin irritation is reduced.
Namely, one of the objects of the present invention is to provide an isosorbide dinitrate-containing patch little in skin irritation and excellent in percutaneous absorption.
Another object of the present invention is to provide an isosorbide dinitrate-containing patch little in skin irritation, excellent in percutaneous absorption and having sustained release.
Further another object of the present invention is to provide an isosorbide dinitrate-containing patch having an adequate degree of adhesive strength and hardly giving pain on the removal of an applied patch.
Still another object of the present invention is to provide an isosorbide dinitrate-containing patch resistant to peeling and stably attached on the skin in use in spite that it has no strong adhesive strength.
Yet another object of the present invention is to provide an isosorbide dinitrate-containing patch which is contrived so as to exhibit excellent handleability even for elderly persons, whose ratio in the patients is high.
The inventors of the present invention have zealously pursued studies for achieving the above-mentioned tasks and completed the present invention by finding that the combination of an acrylic-based adhesive (A), a polyvinyl acetate-based adhesive (B), a plasticizing component (C) and isosorbide dinitrate (D) at specific ratios by weight can attain the objects of the present invention, which can not be achieved by conventional techniques.